Myocardial ischemia and infarction are associated with substantially increased morbidity and mortality among patients with diabetes mellitus. Although many factors contribute to the increased morbidity and mortality, in patients with non–insulin-dependent (type II) diabetes mellitus, one contributor may be the use of sulfonylurea drugs, the most widely used oral hypoglycemic agents. Such a possibility, which first arose over a 25 years ago when it was observed that patients taking sulfonylurea drugs had increased cardiovascular mortality, has recently resurfaced after the discovery that sulfonylureas act by inhibiting adenosine triphosphate (ATP)-sensitive potassium channels. In the pancreas, inhibition of ATP-sensitive potassium channels induces release of insulin; but in the heart, inhibition of these channels prevents ischemic preconditioning, an endogenous cardioprotective mechanism that protects the heart from lethal injury. This review outlines the current understanding of the molecular and cellular pharmacodynamics of sulfonylurea drugs and discusses the potential clinical consequences of inhibition of ATP-sensitive potassium channels in the heart of diabetic patients with cardiac disease in whom the use of sulfonylureas may be harmful.